Anxiety is broadly defined as a state of unwarranted or inappropriate worry often accompanied by restlessness, tension, distraction, irritability and sleep disturbances. This disproportionate response to environmental stimuli can hyperactivate the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, resulting in somatic manifestation of anxiety, including shortness of breath, sweating, nausea, rapid heartbeat and elevated blood pressure (Sanford et al. Pharmacol. Ther. 2000, 88: 197-212). Anxiety disorders represent a range of conditions and as a result have been classified into multiple distinct conditions, including generalized anxiety disorder (GAD), panic attack, post traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD) and social phobias (Sanford et al. Acta. Psychiatr. Scand. Suppl. 1998, 393: 74-80).
Generalized anxiety disorder (GAD) is the most common of the anxiety disorders that is characterized by excessive and persistent worries. In the general population the lifetime prevalence rate of GAD range from 4.1 to 6.6% with somewhat higher rates in woman than in man. The individual with GAD worries about life events such as marital relationships, job performance, health, money and social status. Individuals with GAD startle easily and may suffer from depression. Some of the specific symptoms of GAD include restlessness, motor tension, difficulty concentrating, irritability, and sleep disturbances. The severity of the symptoms over time may be linked to the changing nature of the environmental stressor. With increasing age, GAD symptoms become less severe.
Panic Disorder is a well-studied psychiatric condition that consists of multiple disabling panic attacks characterized by and intense autonomic arousal. In addition, heightened fear and anxiety states occur both during and between panic attacks. Approximately 3% of woman and 1.5% of men have panic attacks. During a panic attack, the individual experiences multiple symptoms including light-headedness, a pounding heart and difficulty in breathing. Panic disorder may be caused by an oversensitive brain system regulating autonomic functions. Potential brain regions involved in panic attack are the locus ceruleus, hippocampus and amygdala. Pathophysiology in the brain GABA-benzodiazepine receptor system may also contribute to the production of panic attack.
Post traumatic stress disorder (PTSD) is another example of a disorder associated with intense fear and anxiety states that require psychiatric treatment. PTSD results from exposure to a life threatening or traumatic event. Individuals with PTSD have recurring thoughts of the terrifying event. Reenactment of the event varies in duration from a few seconds or hours to several days. Individuals with major depression, with panic disorders or lacking strong social supports are vulnerable to develop PTSD
Anxiety disorders, which occur in 10% to 30% of the population, represent not only a significant public health issue but place a substantial economic burden on society. A number of drugs have either been developed or are being developed for treating the different subclasses of anxiety. Some of these agents such as tricyclic antidepressants and b-adrenoreceptor antagonists found either limited use in treating specific disorders such as performance anxiety (e.g., b-adrenoreceptor antagonists suppression of the sympathetic manifestations of anxiety) or have fallen out of favor for reasons of efficacy and/or safety. Currently, direct and indirect serotonin receptor agonists [e.g., selective serotonin reuptake inhibitors (SSRI) and buspirone] and benzodiazepines are most often prescribed for treating anxiety disorders with benzodiazepine receptor agonist being a preferred therapeutic modality. See Atack et al. Curr. Drug Targets. CNS. Neurol. Disord. 2003, 2: 213-232; Stahl et al. J. Clin. Psychiatry 2002, 63: 756-757; Uhlenhuth et al. J. Clin. Psychopharmacol. 1999, 19: 23S-24S; Varia et al. Int. Clin. Psychopharmacol. 2002, 17: 103-107; Vaswani et al. Prog. Neuropsychopharmacol. Biol. Psychiatry 2003, 27: 85-102. The ability of benzodiazepines to enhance g-aminobutyric acid (GABA) neurotransmission safely and rapidly is central to their effectiveness in treating anxiety disorder, especially GAD and panic disorders (Stahl et al. J. Clin. Psychiatry 2002, 63: 756-757). Benzodiazepines act by positively modulating the inhibitory neurotransmitter GABA through an allosteric site on the GABA A receptor complex, a ligand-gated chloride ion channel. Nonetheless, the use of benzodiazepines is limited by side effects associated with enhanced GABAergic neurotransmission, manifesting as sedation, muscle relaxation, amnesia and ataxia. Moreover, the potential for abuse and physical dependence is associated with the long-term use of benzodiazepines. Furthermore, some forms of anxiety such as OCD are relatively resistant to benzodiazepine treatment. These therapeutic limitations and the societal burdens of anxiety provide the impetus for the development of novel anxiolytics or anxioselective agents.
The concept of anxioselectivity is used to describe anxiolysis in the absence of side effects typically associated with benzodiazepines. This search for alternative strategies to treat anxiety disorders have led to the growing use of SSRIs, in addition to a number of other molecular targets including metabotropic glutamate receptors (mGluRs) that are currently under evaluation (Schoepp et al Nat. Rev. Drug Dis. 2005, 4 (2): 131-144. However, none of the alternative targets has been shown to match either the efficacy or rapid onset of benzodiazepine.
The present invention is directed to the D-serine analogs for the treatment of anxiety disorders such as generalized anxiety disorder (GAD), panic attack, post traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD) and social phobias.
It has now been found that compounds of Formula I are useful in the treatment of anxiety related disorders such as those denoted above.